Cancer is a leading cause of disease worldwide and according to a global study on cancer in 2008, an estimated 12.7 million new cancer cases occurred worldwide in that year alone. Of the various types of cancers, breast, lung, bowel and prostate cancers together account for over half of all new cancers worldwide. Accordingly, it is particularly important to develop new and more effective therapies against these particular types of cancer.
Breast cancers can be sub-divided into different subtypes based on whether the tumors express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (Her2). Amongst the various subtypes of breast cancer, Triple-Negative Breast Cancer (TNBC), which is named after its lack of expression of ER, PR and Her2, is one of the most aggressive subtypes of breast cancer with a high propensity for metastasis and is associated with an especially poor prognosis. Owing to the absence of above receptors, no effective targeted therapeutics against TNBC currently exist and current treatment modalities are limited to surgery, radiation and systemic chemotherapy. However, TNBC patients often experience early relapse due to distant tumor metastasis, though they may initially respond well to treatment. Therefore, continued efforts in identifying novel pathways or targets important for TNBC progression and therapy remain a high research priority.
Over the past few decades, tremendous effort has been spent searching for suitable molecular targeted therapies for TNBC, but with limited success. EGFR targeted therapy represents one such example. The rationale for targeting EGFR is based on the observation that TNBC often harbors, EGFR overexpression, leading to hyperactivation of multiple downstream oncogenic kinase signaling pathways such as AKT and ERK. However, EGFR inhibitors have thus far shown limited favorable response during clinical trials. A similar problem was found with poly-ADP ribose) polymerase (PARP) inhibitors which can induce synthetic lethality in BRCA1-deficient TNBC tumors and were thus once believed to be a promising targeted drug for TNBC during early stage clinical trials. However, such inhibitors subsequently failed in a late stage phase III trial.
Although the reasons for the ineffectiveness of these molecular targeted therapies has yet to be determined, one hypothesis is that breast tumors, in particular TNBCs, are highly heterogeneous and utilize multiple mechanisms to enable the aggressive phenotypes, such as invasion and metastasis. These pathways may then get integrated as specific signaling steps that collectively contribute to the disease progression. Pathways and mechanisms involved in invasion and metastasis often involve transcriptional reprogramming induced by deregulated transcriptional regulators, such as NF-κB, ETS1, Notch, TGF-β, and Polycomb protein EZH2, as well as microRNAs such as miR-200s. Downstream targets of these regulators may participate in various rate-limiting steps in disease progression, including epithelial to mesenchymal transition (EMT) (ZEB1/2, TWIST and CDH1), cancer stem cell self-renewal (IL-6 and STAT3), and distant metastasis (Sec23a and VCAM1). Although the breast cancer transcriptome has been extensively investigated, it remains unclear how these pathways are interconnected in disease progression and new regulatory elements crucial for the network integrity need to be identified.
There is a need to provide therapies for treating cancer that overcome, or at least ameliorate, one or more of the disadvantages described above.
There is a need to provide therapies to sensitize and/or re-sensitize a cancer patient who has become resistant to chemotherapy to chemotherapeutic treatment that overcome, or at least ameliorate, one or more of the disadvantages described above.
There is further a need to provide methods to facilitate selection of a suitable treatment for a cancer patient, optimizing the treatment regimen, and prognosis of disease outcome that overcome, or at least ameliorate, one or more of the disadvantages described above.